Diltiazem, 3-(acetyloxy)-5-[2-(dimethylamino)-ethyl)-2, 3-dihydro-2- (4-metoxyphenyl)-1,5-benzotiazepin-4 (5H)-one acetate, is efficacious in angina and hypertension. It is normally used as hydrochloride.
Diltiazem HCl is a white crystalline powder, freely soluble in water. Because of its physico-chemical characteristics, diltiazem is a substance with a pH-dependent solubility.
An oral modified-release pharmaceutical form of diltiazem should exhibit a kinetic of dissolution suitable to ensure blood levels of the drug therapeutically efficacious for the entire time between two subsequent administrations.
Few aspects are of great importance to make the drug-product safe and effective under all the physiological circumstances:
reproducibility of bio pharmaceutical behaviors from batch to batch, PA1 rate of dissolution largely pH-independent, PA1 rate of dissolution largely motility-independent, PA1 rate of dissolution independent from food-intake.
Among the already marketed modified-release products, not all match the above-mentioned requirements.
In-vitro dissolution checks show, in the range of pH between 1 and 7.5, a sharp increase of the release at neutral pH (FIG. 1).
Since the solubility of diltiazem is lower at neutral pH, compared to acidic pH, the observed behavior suggests that in the examined product diltiazem is released by diffusion through an insoluble polymer film, as long as the pH is lower than 7, and by desegregation of the formulation at higher pHs.
A formulation with characteristics as above, in presence of g.i. transit times ranging from few to many hours, may give rise to dose dumping.